Field of the Invention
The present invention relates to a novel process for the preparation of peptidyl heterocyclic ketone derivatives of the general formula (I)

wherein A, R, R1, E and n are as herein defined.
The present invention is further directed to pharmaceutically acceptable salts of the compound of formula (IIa)

The present invention is further directed to processes for the preparation of the compound of formula (IIa) and its pharmaceutically acceptable salts thereof.
The peptidyl heterocyclic ketone derivatives of formula (I) are potent and selective inhibitors of tryptase, useful for the treatment and prevention of inflammatory diseases associated with the respiratory tract, such as asthma and allergic rhinitis, as well as other immunomediated inflammatory disorders such as rheumatoid arthritis, conjunctivitis, psoriasis, inflammatory bowel disease, various vascular and dermatological conditions.
Costanzo et al in PCT publication WO 00/44733 disclose a process for the preparation of compounds of formula (I). However, the process disclosed in the PCT application requires three chromatographic separations, (one in reverse phase), the use of explosive and toxic reagents (in the Dess-Martin oxidation step and HF de-protection), use of cryogenic (−78° C.) temperatures, non-crystalline intermediates, and a product stream that is a mixture of diastereomers requiring separation, which make it unsuitable for large scale manufacture. Thus there exists a need for a process for the preparation of compounds of formula (I) which meets large scale production/manufacturing restrictions.
Berryman et al., in PCT publication WO97/48687 disclose a process for the preparation of chiral keto-heterocycles of basic amino acids.
We now describe a novel process for the preparation of compounds of formula (I) suitable for large scale synthesis. More particularly, the process of the present invention avoids toxic and/or explosive materials, does not require cryogenic temperatures, and/or does not require chromatographic separations. The process of the present invention may also be applied to yield a final product wherein one stereoisomer predominates.